New classes of medication for the treatment of serious mood and anxiety disorders have not been discovered for decades. Current medication treatment for these disorders is dominated by the selective serotonin reuptake inhibitors (SSRIs). However, SSRIs while an improvement in safety and tolerability over older medications such as the tricyclic antidepressants, have not resulted in improved efficacy. Advances in our understanding of the pathophysiology of mood and anxiety disorders, gleaned from both preclinical and clinical neuroscience research, have now set the state for testing the antidepressant and antianxiety efficacy of several new classes of medications. In the proposed project, investigators in the NIMH Intramural Mood and Anxiety Disorders Research Program, in collaboration with scientists from the Emory University School of Medicine and the pharmaceutical company GlaxoSmithKline, will evaluate the therapeutic potential of a CRF1 receptor antagonist (SB723620), a NK-1 receptor agonist (GW597599), a SSRI/5HT1A agonist (vilazodone), and a type IV phosphodiesterase inhibitor (SB207499) using an open trial proof of concept design in two patient groups, major depression and post traumatic stress disorder. Medications which show the potential for clinically relevant therapeutic effects will subsequently be tested in multicenter, placebo-controlled investigations. A major impediment to progress in the discovery and clinical trial testing of novel medications for serious psychiatric disorders is the lack of surrogate neurobiological markers predictive of therapeutic response. Identification of such markers could greatly facilitate drug discovery and may reduce the number of patients required for pivotal clinical trials. Therefore, in the proposed project we will also examine the usefulness of several potential neurobiological surrogate markers for antidepressant/antianxiety efficacy utilizing functional and receptor neuroimaging, psychophysiological and neuroendocrine techniques.